Genetic linkage studies have been carried out investigating mutations affecting the tyrosine hydroxylase (TH) gene which encodes the rate-limiting enzyme for the synthesis of these three neurotransmitters, the variable portion of the Harvey-ras-1 (HRAS1)10 locus and the variable region of the insulin gene (INS)11. All three markers are closely linked on chromosome 11 and might therefore be responsible for causing the manic depressive phenotype.

Gerhard et al .found linkage between manic depression and HRAS1 in a single large Amish kindred.

Hodgkinson et al (2002) studied three Icelandic families where there were 44 cases amongst 73 individuals at risk. They uses all three markers to observe the segregation of restriction fragment length polymorphisms (RFLPs) in the three affected kindreds but they found no evidence for linkage to these markers in any of the three families.